A silver lining for 24-hydroxycholesterol in Alzheimer's disease: The involvement of the neuroprotective enzyme sirtuin 1

Abstract

It is now established that cholesterol oxidation products (oxysterols) are involved in several events underlying Alzheimer's disease (AD) pathogenesis. Of note, certain oxysterols cause neuron dysfunction and degeneration but, recently, some of them have been shown also to have neuroprotective effects. The present study, which aimed to understand the potential effects of 24-hydroxycholesterol (24-OH) against the intraneuronal accumulation of hyperphosphorylated tau protein, stressed these latter effects. A beneficial effect of 24-OH was demonstrated in SK-N-BE neuroblastoma cells, and is due to its ability to modulate the deacetylase sirtuin 1 (SIRT1), which contributes to preventing the neurotoxic accumulation of the hyperphosphorylated tau protein. Unlike 24-OH, 7-ketocholesterol (7-K) did not modulate the SIRT1-dependent neuroprotective pathway. To confirm the neuroprotective role of 24-OH, in vivo experiments were run on mice that express human tau without spontaneously developing tau pathology (hTau mice), by means of the intracerebroventricular injection of 24-OH. 24-OH, unlike 7-K, was found to completely prevent the hyperphosphorylation of tau induced by amyloid β monomers. These data highlight the importance of preventing the loss of 24-OH in the brain, and of maintaining high levels of the enzyme SIRT1, in order to counteract neurodegeneration.Graphical abstractA hypothetical scheme of the molecular mechanisms underlying the effects of 24-OH on hyperphosphorylated tau accumulation.

Revealing a Novel Landscape of the Association Between Blood Lipid Levels and Alzheimer's Disease: A Meta-Analysis of a Case-Control Study

“…For example, 24-hydroxycholesterol (24-OHC) can impede hyperphosphorylation of tau induced by deposition of Aβ in SK-N-BE cells by regulating the deacetylase sirtuin 1. As a neuroprotective oxysterol, 24-OHC was also validated to modulate synaptic function in hippocampal neurons of rats through LXR (Testa et al, 2018). Furthermore, genomewide association studies (GWAS) verified that some genes like ABCA7, TREM2, DAPK1, and ADAMTS1 were associated with AD.…”

7-Ketocholesterol and 7β-hydroxycholesterol: In vitro and animal models used to characterize their activities and to identify molecules preventing their toxicity

“…In these cells, 7KC-induced cell death was attenuated by 24S-OHC [109]. Human SK-N-BE neuroblastoma cells were also treated with 7KC at the physiopathological concentration of 1 µM with the aim of comparing the effects of 7KC and 24S-OHC on tau phosphorylation, and to study the abilities to modulate the SIRT1-dependent neuroprotective pathway [110]. SK-N-BE cells were also used to compare the cytotoxicity of 7KC and 7β-OHC.…”

A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease

“…As regards 24-OHC, contrasting effects have been reported: on the one hand it promotes neuroinflammation, Aβ peptide production, oxidative stress, and cell death in neuronal cell lines (Gamba et al, 2011, 2014; Yamanaka et al, 2011; Testa et al, 2014); on the other hand, it has been reported to play an important role in regulating brain cholesterol metabolism via LXR, and to exert beneficial effects such as preventing tau hyperphosphorylation in SK-N-BE cells, suppressing Aβ production in SH-SY5Y cells, and regulating synaptic function in rat hippocampal neurons and slices (Paul et al, 2013; Urano et al, 2013; Testa et al, 2018b). These opposite effects may depend on 24-OHC concentration, since low concentrations (1–10 μM) seem to induce adaptive responses and beneficial effects in neuronal cell lines as discussed by Testa et al (2018a).…”